Reference is made in this specification, by way of superscripted numerals, to a number of publications listed at the end of the disclosure.
Numerous drugs exist which cannot be administered systemically due to their water insolubility, toxicity and/or instability. Many of these drugs are also sensitive to oxidation, including but not limited to, 5-amino salicylic acid, aminoglucoside antibiotics, flucytosine, pyrimethamine, sulfadiazine, dapsone, trimethoprim, mitomycins, methotrexate, doxorubicin, daunorubicin and polymyxin B. Peptides containing oxidation sensitive amino acids such as cysteine, methionine, tyrosine, histidine and tryptophan .sup.(1) and amino acid ester derivatives of hydroxyl containing oxidizable drugs which contain a primary amine are also sensitive to oxidation. One solution for stabilizing such drugs is to conjugate them to a carrier.
Water soluble, oxidized polysaccharides such as, for example, dextrans are considered to be one of the most attractive drug carrier candidates .sup.(2). Dialdehydedextran (DAD), the main product of the oxidation reaction of periodate with dextran, has been proposed as a stabilizer for enzymes and drugs, including antibiotics .sup.(3-8). However, oxidation-sensitive drugs such as those listed above lose a major portion of their biological activity following conjugation.
GB 978,170 describes a process for the preparation of water-soluble imine derivatives of polyene antibiotics, in which a polysaccharide is oxidized to a polydialdehyde prior to being reacted with the polyene. Among the conjugates described in this patent are pimaricin-dextran and Nystatin-corn starch. No amine conjugates are described in the British patent.
In experiments carried out by the applicant of the present application, and described in Example XI below, it was found that although a Nystatin-dextran conjugate prepared according to the process described in the above patent is water-soluble, it has very low stability and activity, and is susceptible to drastic degradation of the polymer and inactivation of the conjugated drug. It is believed that this is due to the fact that the oxidized polymer is not purified from excess oxidizing agent prior to conjugation, thus resulting in the polyene undergoing oxidation. This purification was found to be essential for the stability, efficacy and lack of toxicity of the conjugated drug, as will be further described below.